The global burden of cancer doubled between 1975 and 2000. Cancer became the leading cause of death worldwide in 2010, and is projected to double again by 2020 and to triple by 2030. This horrible disease has touched each of us, and despite enormous investments in prevention and treatment, its impact continues to accelerate. Ideally, any cancer therapy should be effective (at killing cancerous cells), targeted (i.e. selective, to avoid killing healthy cells), and permanent (to avoid relapse and metastasis). Today's standards of care for most cancers fall short in some or all of these criteria. We have developed a novel therapy (chNKG2D T cells) that has met these marks in animal models through the use of the host's own immune cells. A patient's T-cells are modified to express chimeric NKG2D (chNKG2D) receptors, expanded, and then returned to the patient. We believe that this innovation will lead to a new class of therapies with remarkable potential, and we are actively developing it for therapy of several tumors including myeloma, lymphoma, and ovarian cancer. To date we have: demonstrated the ability to achieve 100% survival and 100% durable protection against tumor rechallenge in murine models of multiple myeloma, lymphoma, and ovarian cancer, established the MTD for single and multiple doses, identified biomarkers for use in the clinic, demonstrated equivalent function post- cryopreservation, developed protocols for expansion in serum-free media, designed and sequenced the human vector, expanded human cells in standard and gas permeable flasks, conducted a pre-IND meeting with FDA, written >80% of the IRB, RAC, and IND documents, and engaged a world-class clinical team. This grant will take chNKG2D T cells into the clinic, and if successful will yield a therapy ready for Phase II clinical trials. Herein we propose to complete the remaining preclinical development and conduct a Phase I clinical trial. We will produce and qualify a master cell bank using pSFG-chNKG2D in PG13 packaging cells as well as >9 liters of GMP/clinical grade vector, complete clinical trial preparations by: Generating an antibody to chNKG2D and a qPCR assay for PKPD studies, Developing protocols for clinical scale production of chNKG2D T cells and defining clinical SOPs, and Determining mechanisms associated with toxicity of chNKG2D T cells and their survival in vivo. In Year Two of this grant we will conduct a Phase I clinical trial, enrollig patients with both liquid and solid tumors and conducting a dose escalation to determine toxicity and MTD, and gain further insight into mechanism of action.